Science & Medicine

JAK at ASH…A PROLIFERATION OF Uninhibited PROMISE

The JAK inhibitor, once thought to be our magic MPN bullet — then briefly tossed aside on the scrapheap of lost expectations — has risen again with a vengeance!

The surprising JAK inhibitor update from ASH…

by Zhenya Senyak

For MPN patients, particularly intermediate to high risk MF patients, JAK inhibition means interrupting downstream signalling to the blood production systems. This process can improve quality of life by rapidly shrinking the spleen, most likely extending longevity, reducing or eliminating many constitutional effects and, in some configurations, reducing or eliminating the need for blood transfusion.

These same JAK inhibitors are likely to cause or worsen anemia, reduce platelet levels, produce peripheral neuropathy, sometimes strong enough to cause cessation of therapy and a variety of other unfortunate effects euphemistically known as SAE’s, or Serious Adverse Events.

The growing popularity of JAK inhibitors however is not hard to understand.

For some, JAK inhibition is simply the quickest, safest and best option. Among higher risk MF patients – and to some extent all MPN patients – treatment options (beyond stem cell transplant) boil down to three: cytotoxic chemotherapy (hydroxyurea), biologically derived drugs (the injectable interferons that are effective long-term at low dose levels) and rapidly acting, genetically targetted drugs (the oral JAK inhibitors). There are variations and supplements designed to relieve specific symptoms but it does seem to boil down to these limited but promising choices.

Here are three JAK inhibitors that made a splash at ASH: Incyte’s Jakafi, YM Bioscience’ CYT387, and Sanofi’s SAR302503.

JAKAFI

For Jakafi we had a ringside seat. From the time ruxolitinib surfaced at ASCO in 2011 with the promise, finally, of a drug for MF treatment, it was the MPNforum lead story. Principal investigators, Srdan Verstosek, Ruben Mesa and Claire Harrison all contributed insights, slides, and comments to the MPN community. We interviewed Incyte CEO Paul Friedman and learned we weren’t after all the real target of this multimillion dollar investment, just the beneficiaries. We followed the COMFORT trials in the US and Europe like a life and death football match…which for some of us, of course, it was.

We were in New York when the FDA approved Jakafi a little more than a year ago and we’ve seen many of our friends and MPN neighbors get on the drug and rapidly improve. We’ve seen some who had to get off when it stopped working for them and we’ve seen some who couldn’t get on because of physician or insurance company concerns.

The Janus Kinases – JAK1, JAK2, JAK3 and TYK2 — are involved in signalling pathways for multiple biologic functions. It’s that pathway – the JAK-STAT pathway that leads from signal into the heart of the cell’s nucleus to signal the DNA to produce new proteins — that is the real target. Myelofibrosis patients were primarily “lucky” enough to need a drug badly enough that the FDA approval process would be much faster than that required for more common disease like, say, rheumatoid arthritis. The inflammatory response to cytokine signals, now believed by many to be involved in marrow fibrosis as well as some auto-immune diseases, can be dampened by interruption. And so the money piled in fueling research and clinical trials.

Unfortunately, there has not yet been a laser aiming device that would select JAK2, the JAK most involved in blood production. Jakafi does interrupt JAK2 functioning but does it with a shotgun pattern that interrupts innocent bystanders, often producing adverse effects like anemia, thrombocytopenia, and peripheral neuropathy.

But there was an unintentional creative benefit from this scattershot. Something in the firing pattern of the first JAK inhibitors affected all participants pretty much equally. While only about 50% of MF patients treated had the V617F JAK mutation, all benefited, regardless! Clearly there was something else happening and the hunt was on.

Jakafi at ASH

While other drug firms continued development and testing of their own JAK inhibitor molecules, Incyte and its partner, Novartis, had the field to itself and quickly established a patient base and supporting physicians. Incyte also continued testing Jakafi to see what effect it has on longevity, how low a platelet level is necessary to disqualify a patient, etc. The preliminary results were reported at ASH 20012. The effect on longevity extension seems to be confirmed, combinatorial trials with Jakafi are being designed and safe platelet levels have been reduced to 50,000.

While Jakafi seems positioned to be the sole approved JAK inhibitor for MF patients through most of 2013, there are competing molecules rolling up to the launch pad.

CYT387

It looks like a made in Australia drug once known as Cytopia, brought through clinical trial by a Canadian company, YM Biosciences, will be taken through Phase III trial and marketing by still another group, an American Aids drug maker. The day after Animesh Pardenani’s presentation at ASH, California based Gilead Sciences announced its half billion dollar bet on the success of CYT387. That amount works out to a little over $16000 for each MF patient in the United States and Europe. (YM Biosciences’ stock value soared, Gilead’s dropped a bit.)

Still, it could be a winner. CYT387 reported excellent results on two fronts – anemia and blood transfusion – and seems to have proven its molecule is targeting the specific JAK2 target enzyme without seriously impacting other related tyrosine kinases. As a result CYT387 presented data showing significant reduction of the need for transfusion within the high risk MF patient population.

Click below to hear Dr. Animesh Pardanani’s full CYT387 presentation

Whether or not CYT387 is too late to market to overcome Jakafi’s long lead and established patient base, the real payoff for Gilead in purchasing YM Biosciences is likely not in the myeloproliferative arena at all.

JAK-Stat Pathway, Source Nature Reviews, Immunology

That same JAK-STAT pathway used in hematopoiesis is also a player in inflammatory and auto-immune diseases like rheumatoid arthritis, psoriasis and ulcerative colitis. The market for an oral JAK1/JAK2 inhibitor for RA alone is estimated at over $10 billion with a global RA market approaching $40 billion in the next five years. Gilead has both the deep pockets and marketing infrastructure to push development and distribution of CYT387 – by whatever name it will be called at the end. So do Incyte and its partner, Novartis. So while we may not be the primary target of all this muscle, we seem certain to be the beneficiary of the next generation of JAK inhibitors.

Reverse Fibrosis? Sanofi’s SAR302503

An intriguing glimpse at one contender in the new generation of JAK inhibitors appeared as the results of a Phase II trial of Sanofi’s SAR302503 were published. This is the same molecule we knew as TargeGen T101348, specifically tailored to zero in on JAK2, blocking downstream signaling for blood production.

Although the Sanofi cohort of 31 was too small to draw firm conclusions, it was clear that the Sanofi offering could produce impressive constitutional results with little incidence of thrombocytopenia. At trial dosages of 300mg, 400mg, and 500mg, the incidence was 20%, 9%, and 0%, respectively. It is counter-intuitive that the higher dosage produced the fewest cases of thrombocytopenia but that’s a drawback of a small sample. The results mean the Phase III trial, called JAKARTA, can include patients who currently have platelet levels as low as 50,000.

The Phase III JAKARTA trialis ready to roll with a cohort of 291 patients divided into three arms (300mg, 400mg, and placebo) Results are expected in the third quarter of 2013 but Sanofi will be at ASCO in Chicago May 31-June 4) with a preliminary report.

The buzz – based on anecdotal data confirmed by Dr. Pamela Cohen, Project Director and Associate VP of Clinical Research at Sanofi Oncology – is that the Sanofi JAK inhibitor has succeeded in reducing bone marrow fibrosis “up to two grades including complete reversal in some cases.” If that proves out in clinical trial, the drug would change the MPN research and development landscape and offer an undeniable advantage to patients. We should know in six months.